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Ligand-induced down-regulation of trk messenger RNA, protein and tyrosine phosphorylation in rat cortical neurons

1997; Elsevier BV; Volume: 78; Issue: 3 Linguagem: Inglês

10.1016/s0306-4522(96)00616-1

1873-7544

Beat Knüsel, Hua Gao, Takashi Okazaki, Takushi Yoshida, Naoko Mori, Franz Hefti, David R. Kaplan,

Retinoids in leukemia and cellular processes

Chronic exposure of brain neurons to nerve growth factor in vitro and in vivo results in increased levels of the nerve growth factor receptor TrkA. In contrast, in the present study, we have found that chronic exposure of rat embryonic cortical neurons to brain-derived neurotrophic factor leads to a pronounced reduction of the levels of protein and messenger RNA for the full-length but not the truncated brain-derived neurotrophic factor receptor TrkB. Similar effects were observed with the other TrkB ligands neurotrophin-3 and neurotrophin-4/5. After pretreatment with brain-derived neurotrophic factor, neurotrophin-3 or neurotrophin-4/5, subsequent tyrosine phosphorylation responses of the remaining Trks to the same factors were greatly reduced. Three days exposure of rat embryonic cortical neurons to brain-derived neurotrophic factor induced an absolute refractory period of several hours, with no subsequent response to the same factor. Similar but less pronounced refractory effects were observed with neurotrophin-3 and neurotrophin-4/5. Our results suggest a negative regulatory effect of brain-derived neurotrophic factor and other TrkB ligands on TrkB receptors. Down-regulation of the TrkB response by its ligands might play a role in the control of brain-derived neurotrophic factor action during early development, when brain-derived neurotrophic factor levels significantly increase. Our findings are also of potential clinical relevance, since the possibility of ligand-induced down-regulation of the receptor response needs to be addressed when considering brain-derived neurotrophic factor or other neurotrophins for the therapy of neurodegeneration, e.g., in Parkinson's disease.